1-(hydroxy-1-phenyl-4-aminobutenyl)adamantane derivatives

ABSTRACT

1-(1-Hydroxy-1-phenyl-4-aminobutyl)-and 1-(1-phenyl-4aminobutenyl)-adamantane derivatives in which the phenyl ring may be chloro, trifluoromethyl, methyl, methoxy or methylthio substituted and the amino group may be dilower-alkylamino, Npiperidinyl, N-pyrrolidinyl, N&#39;&#39;-lower alkyl-N-piperazinyl or Nmorpholinyl are useful as tranquilizers. The compounds are generally prepared by reaction of an appropriate 1-adamantyl phenyl ketone with an aminopropyl magnesium halide to give the hydroxybutanes followed by acid dehydration to furnish the butene derivatives.

United States Patent Kaiser et al.

[451 July 11, 1972 [541 1-(HYDROXY-1-PHENYL-4- AMINOBUTENYL)ADAMANTANEDERIVATIVES [72] Inventors: Carl Kaiser, Haddon Heights, N.J.; v CharlesL. Zirkle, Berwyn, Pa.

[73] Assignee: Smith Kline & French Laboratories,

' Philadelphia, Pa.

[22] Filed: Aug. 12, 1970 [21] Appl.No.: 63,266

Related U.S. Application Data [62] Division of Ser. No. 715,507, March25, 1968, Pat.

[52] U.S. Cl ..260/240 TC, 260/247.7 A, 260/268 TR, 260/293.62,260/5706, 260/70.8 TC, 260/591,

[51] Int. Cl ....C07d 29/16, C07d 29/12 [58] Field of Search ..260/240TC, 570.8 TC

[56] References Cited UNITED STATES PATENTS 3,553,225 1/ 1971 Kaiser etal ..260/240 TX Primary Examiner-John D. Randolph Atr0meyWilliam H.Edgerton, Richard D. Foggio, Joan S. Keps, Arthur R. Eglington, Alan D.Sourie and Joseph A. Marlino [5 7] ABSTRACT 3 Claims, No Drawings l-(IIYDROXY- l -Pl-IENYL-4- AMINOBUTENYDADAMANTANE DERIVATIVES Thisapplication is a division of application Ser. No. 715,507 filed Mar. 25,1968 now US. Pat. No. 3,553,225 granted Jan. 5, 1971.

This invention relates to novel l-(l-hydroxy-l-phenyl-4- aminobutyl)-and l-( l-phenyl-4-aminobutenyl)-adamantane derivatives having usefulpharmacodynamic activity. More specifically the compounds of thisinvention have tranquilizing activity as demonstrated in standard animalbehavioral test procedures. Exemplary of the activity shown'by thecompounds of this invention is the decrease in shock-motivated behaviorin squirrel monkeys at oral dosages of from 05-20 mg/kg. This activityis characteristic of chlorpromazine-lilte tranquilizers.

The compounds of this invention are represented by the following generalstructural formulas:

CCH(CH2)2Z Formula II Formula I in which:

Y represents hydrogen, chlorine, trifluoromethyl, methyl,

methoxy or methylthio; and

Z represents diloweralkylamino, N-piperidinyl, N-pyrrolidinyl, N'-loweralkyl-N-piperazinyl or N-morpholinyl.

By the term lower alkyl where used herein, groups havin from one tothree carbon atoms are indicated.

The compounds of this invention may be used in the form of apharmaceutically acceptable acid addition salt having the utility of thefree base. Such salts, prepared by methods well known to the art, areformed with both inorganic or organic acids, for example: maleic,fumaric, benzoic, oxalic, ascorbic, pamoic, succinic,bismethylene-salicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicyclic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-aminobenzoic, glutamic, benezenesulfonic, hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.

The compounds of this invention are generally prepared by reaction of anappropriately substituted phenyl l-adamantyl ketone with an aminopropylmagnesium halide (Grignard reagent) to give the hydroxybutyl compoundsof formula I. Dehydration of the latter yields the butenyl compounds offormula II. The reaction sequence is shown in the following scheme:

l-HaO More specifically, the above Grignard reaction is advantageouslycarried out in tetrahydrofuran solution, although other similarnonreactive organic ether-type solvents may be employed, at refluxtemperature for from 1 to 4 hours. Usual workup procedures such ashydrolysis with for example aqueous ammonium chloride solution yieldsthe amino-butanol products. The latter are dehydrated advantageously bytreatment with acid such as a mineral acid, for example hydrochloric orsulfuric acid, preferably at reflux for from 1 to 8 hours to give theaminobutene products.

The phenyl l-adamantyl ketone starting materials used as describedhereinabove are either known or are prepared by methods known in theart. Thus following the procedure of Stetter and Rauscher, Ber. 93, l161 (1960), l-adamantanecarboxylic acid chloride is reacted with aY-substituted diphenyl cadmium derivative to give the desired ketone.

The compounds of this invention may be administered orally orparenterally in conventional dosage unit forms such as tablets,capsules, injectables or the like, by incorporating the appropriate doseof a compound of formulas l or II with carriers according to acceptedpharmaceutical practices.

The foregoing is a general description of how to prepare the compoundsof this invention. It will be apparent to one skilled in the art thatthe compounds of formula I can be present as optical isomers and thecompounds of formula II as cis-trans isomers. Where desired theseisomers can be separated by standard organic chemical techniques. Unlessotherwise noted herein, the description and the attached claims areintended to include mixtures of such isomers as well as the separatedisomers themselves.

The following examples illustrate the preparation of specific compoundshaving tranquilizing activity. However this should not be construed aslimiting the scope of the invention since appropriate variations in thestarting materials will produce other corresponding products disclosedabove.

PREPARATIONS A. l-Adamantyl phenyl ketone A solution of 67 ml. (0.2 m.)of 3M phenyl magnesium bromide in 130 ml. of ether under nitrogen iscooled in an ice bath and 18.9 g. (0.103 m.) of anhydrous cadmiumchloride is added. The mixture is allowed to come to room temperature,refluxed for minutes and then ml. of dry benzene is added. The ether isremoved (trap) and 28.9 g. (0.145 m.) of l-adamantanecarboxylic acidchloride in 100 ml. of dry benzene is added over 15 minutes. Theresulting mixture is stirred and refluxed for one hour, then cooled inan ice bath. Cold water (75 ml.) is added slowly, followed by 20 percentsulfuric acid solution until the appearance of two layers. The aqueouslayer is extracted with ether and the extract combined with the organiclayer which is washed with water and a saturated sodium chloridesolution. The dried solution is evaporated to give l-adamantyl phenylketone, m.p. 43-46 C. B. l-Adamantyl Y-substituted phenyl ketones Byemploying in Part A, Y-substituted phenyl magnesium bromide preparedfrom bromobenzenes such as noted below, there is obtained thecorresponding l-adamantyl Y-substituted phenyl ketone startingmaterials:

2,3 or 4-bromochloroben2ene 2,3 or 4-bromobenzotrifluoride 2 or4-bromotoluene 4-bromoanisole 4-brornothioanisole.

EXAMPLE 1 To 1.2 g. of magnesium in 5 ml. of tetrahydrofuran is added 10ml. ofa solution of 8.1 g. (0.05 m.) of l-( 3-chloropropyl)- piperidinein tetrahydrofuran and the mixture is refluxed for 90 minutes. Themixture is cooled in an ice bath and 7.2 g. (0.03 m.) of l-adamantylphenyl ketone in 30 ml. of tetrahydrofuran is added. After refluxing for90 minutes the reaction mixture is poured into a solution of 7 g. ofammonium chloride in 250 ml. of cold water with stirring. The resultingmixture is extracted with ether and the dried extract evaporated to give1[ l-hydroxy-l-phenyl-4-( N-piperidinyl)- butyl]-adamantane, m.p.l08-l09 C.

Similarly, by employing an equivalent amount of l-adamantyl 2,3 or4-chlorophenyl ketone in the above reaction there is obtained thecorresponding l-[ l-hydroxy-l-(2,3 or 4-chlorophenyl)-4-(N-piperidinyl)-butyl]-adamantane derivative,respectively.

EXAMPLE 2 A mixture of 6.0 g. (0.16 m.) of 1-[hydroxy-l-phenyl-4-(N-piperidinyl)-butyl]-adamantane and 75 ml. of concentrated hydrochloricacid is stirred and refluxed for 90 minutes. The reaction mixture isconcentrated in vacuo, dissolved in water, made basic and extracted withether. The ether extract is evaporated to give I-[l-phenyl-4-(N-piperidinyl)-butenyl]- adamantane, maleate salt m.p.l96l98 C.

Similar treatment as described above of the chlorophenyl analoguesprepared as in Example 1, yields the corresponding 1-[ l-( 2,3 or4-chlorophenyl)-4-(N-piperidinyl)-butenyl]-adamantane derivative,respectively.

EXAMPLE 3 Following the procedures of Examples 1 and 2,l-adamantyl4-trifluoromethylphenyl ketone is reacted with the Grignardreagent formed from 3-(dimethylaminopropyl)- chloride to give l-[l-hydroxy-l-(4-trifluoromethylphenyl)-4-(N,N-dimethylamino)-butyl]-adamantane which is dehydrated withhydrochloric acid to the l-[l-(4- trifluoromethylphenyl)-4-(N,N-dimethylamino)-butenyl1- adamantane.

EXAMPLE 4 Following the procedures of Examples l and 2, l-adamantyl2-tolyl ketone is reacted with the Grignard reagent formed froml-(3-chloropropyl)-pyrrolidine to give l-[ l-hydroxy-( l-(2-tolyl)-4-(Npyrrolidinyl)-butyl]-adamantane which is dehydrated bytreatment with hydrochloric acid to yield 1-[ l- (2-tolyl )-4-(N-pyrrolidinyl )-butenyl l-adamantane.

Similarly, use of l-adamantyl 4-tolyl ketone as described above resultsin the formation of 1-[ l-hydroxy-l-(4-tolyl)-4-(N-pyrrolidinyl)-butyl]-adamantane and l-[l-(4-tolyl)-4-(N- pyrrolidinyl)-butenyl ]-adamantane.

EXAMPLE 5 Following the procedures of Examples 1 and 2, l-adamantyl4-methoxyphenyl ketone is reacted with the Grignard reagent formed froml-( 3-chloropropyl)-morpholine to give 1-[lhydroxy-1-(4-methoxyphenyl)-4-(N-morpholinyl)-butyl]- adamantane whichis dehydrated with hydrochloric acid to the l-[l-(4-methoxyphenyl)-4-(N-morpholinyl)-butenyl]-adamantane.

EXAMPLE 6 Following the procedures of Examples 1 and 2, l-adamantyl4-methylthiophenyl ketone is reacted with the Grignard reagent formedfrom N-(3-chloropropyl)-N'-methyl-piperazine to givel-[l-hydroxy-1-(4-methylthiophenyl)-4-(N'-methyl-N-piperazinyl)-butyl]-adamantane which is treated with hydrochloric acidto give the dehydrated product, I-[ l-(4-methylthiophenyl)-4-(N'-methyl-N-piperazinyl)-butenyl]- adamantane.

What is claimed is:

l. A chemical compound having the following formula

2. A chemical compound according to claim 1 in which Y is hydrogen.
 3. Achemical compound according to clam 1 in which Z is N-piperidinyl, beingthe compound 1(1-phenyl-4-(N-piperidinyl)-butenyl)-adamantane.